The incidence of glucose intolerance and obesity-related Type 2 diabetes increases with age. The mechanisms of age-related glucose intolerance are not clear, but it appears to be related to both impaired b- cell function and decreased insulin sensitivity. Identification and characterization of the genes involved in obesity and diabetes will add essential knowledge to our understanding of the mechanisms of diabetes and lead to interventions that can improve the quality of life in the elderly. Ghrelin is the only circulating peptide known to stimulate appetite and; thereby, promote obesity. We generated and characterized ghrelin-null mice; unexpectedly adult ghrelin-/- mice are not protected against diet-induced obesity. It was surprising to find that ghrelin inactivation augments insulin secretion in response to glucose challenge and increases peripheral insulin sensitivity. Ghrelin and leptin are mutual antagonists in energy homeostasis. Leptin-deficient mice (ob/ob) are hyperphagic, obese and hyperglycemic. To investigate the interplay between ghrelin and leptin, we also generated ghrelin-deficient ob/ob mice. The inactivation of ghrelin in ob/ob mice fails to rescue the obese hyperphagic phenotype, which indicates that the ob/ob phenotype is not a consequence of ghrelin unopposed by leptin; however, despite their similar body weights, blood glucose is markedly reduced in ghrelin-/-.ob/ob mice. Our data suggest that low ghrelin levels may have a beneficial effect for diabetes patients. Our preliminary studies show that ghrelin levels may increase with age in mice, so we hypothesize that higher ghrelin levels contribute to a higher incidence of diabetes during aging. Ghrelin antagonists may; therefore, prevent and/or reduce the Incidence of Type 2 diabetes during aging. The specific aims of this proposal are 1) to use our unique mouse models to identify the regulators which mediate ghrelin's effect on the worsened glucose intolerance in aging mice and 2) to subsequently determine if their expression is regulated by ghrelin and correlated with age. These studies will shed more light on the molecular mechanisms of diabetes and glucose homeostasis during aging, and may potentially lead to the discovery of new means for the prevention and/or treatment of aging-related diabetes. [unreadable] [unreadable] [unreadable]